There have been heretofore known, as an indian hemp ingredient, a series of compounds called cannabinoid, consisting of C, H and O. Of these, tetrahydrocannabinol (THC) is considered to be the hallucinogen, and the main ingredient contained in hemp is known to be .DELTA.9-THC. The .DELTA.9-THC has been observed to cause pharmacological actions such as ataxia, increase in irritability, suppression of emesis, analgetic action, body temperature fall, suppression of respiration, induction of catalepsy, vasodilation, immunosuppressive action and the like.
The mechanism of these pharmacological actions is considered to mainly concern central nervous system (Devane et al., Mol Pharmacol. 1988,34,605-613; Hollister et al., Pharmacol. Rev., 1986,38, 1-20; Renv et al., Prog. Drug. Exp. Ther., 1991, 36, 71-114) and peripheral cells (Nye et al., J. Pharmacol. Exp. Ther., 1985, 234, 784-791; Flynn et al., Mol Pharmacol. 1992, 42, 736-742), and part of the action through the central nervous system has been reported to be applicable to the medical care.
In particular, the development of an agonist of peripheral cell receptor such as one having antiinflammatory action, antiallergic action and nephritis therapy effect in addition to its immunoregulating action by regulating immunoreaction has been expected based on the finding of a receptor on macrophage (Munnro et al., Nature, 1993, 365, 61-65).
As the agonist of the cannabinoid receptor, pyrazole derivatives (Japanese Patent Unexamined Publication No. 73014/1994, EP 656354, EP 658546), THC derivatives (Japanese Patent Unexamined Publication No. 209377/1991), benzoxazine derivatives (U.S. Pat. No. 5,112,820), indole derivatives (U.S. Pat. No. 5,081,122) and fatty acid derivatives (WO94/12466) are known.
There have been documented various reports on amide derivatives. For example, Japanese Patent Unexamined Publication No. 54/1986 discloses 5-lipoxygenase inhibitors such as benzoylamino acid amide; Japanese Patent Examined Publication No. 49686/1994 discloses an intermediate compound, allyl-ethylbenzamide; Japanese Patent Unexamined Publication No. 85137/1977 discloses 2-butoxyphenyl-ethylbenzamide as a hypoglycemic; Japanese Patent Unexamined Publication No. 131846/1976 discloses 2-butoxyphenyl-ethylbenzamide bezoic acid as a hypoglycemic benzoic acid derivative; Japanese Patent Unexamined Publication No. 213877/1993 discloses N-acetyl-3,4-bis(heptyloxy)-N-(2-pyridinylmethyl)benzamide as a platalet activator inhibitor, Japanese Patent Examined Publication No. 31852/1971 discloses 1-(N)-methyl-2-(4'-butoxy-2',6'-dimethylbenzoylamino)-methyl-piperidine as a local anesthetic; Japanese Patent Unexamined Publication No. 137972/1975 discloses 4-butoxy-N-(3-pyridyl)-benzamide as an antitubercular agent; U.S. Pat. No. 4,743,610 discloses amino-alkoxy-pyridinyl-alkyl-benzamide as a thromboxane synthesis inhibitor, and Japanese Patent Unexamined Publication No. 85963/1989 discloses alkoxy-naphthalenyl-pyridinyl-amide as a platelet activator inhibitor. However, these publications do not teach pharmacological actions based on the action mechanism via cannabinoid receptors.
It is therefore an object of the present invention to provide a novel compound which selectively acts on a cannabinoid receptor, particularly a peripheral receptor, and which is free of the above-mentioned problems, and pharmaceutical use thereof.
More particularly, an object of the present invention is to provide a novel compound which selectively acts on a cannabinoid receptor, particularly, peripheral cells, which has immunoregulating action, antiinflammatory action, antiallergic action and nephritis therapy effect, and which is associated with less effects on the central nervous system (e.g., side effects such as excitation, hallucination, ataxia, increase in irritability, body temperature fall, suppression of respiration, induction of catalepsy, blood pressure elevation and the like), and pharmaceutical use thereof.